Thyroid, Food Addiction, and the Metabolically Unfit Fat Cell

The following are the lecture notes from a talk I gave back in 2005 to the American Society of Bariatric Physicians. The information is just as valid today as it was then – as a number of newer studies continue to prove these points – especially regarding food cravings and food addiction. This file contains extensive information that is of value for any person seeking a more in-depth understanding of this important subject.

Byron Richards is a Board Certified Clinical Nutritionist, in private practice in the Minneapolis area since 1985. As a pioneer in the field of applied clinical nutrition he has helped thousands recover their health with improved nutrition. His areas of special expertise include weight loss, thyroid problems, fibromyalgia, chronic fatigue, and all hormone-related issues. He is heard weekly on WCCO radio, providing informative and useful tips on natural ways to improve health. He is the author of the groundbreaking book, “Mastering Leptin.” Today, he will help us understand the complexity and diversity of this hormone; as well as provide insights on how to use this information to help individuals lose weight healthfully.

Abstract

Leptin is the hormone produced by fat cells. In healthy metabolism it crosses the blood brain barrier and signals the hypothalamus gland that adequate fuel is in reserve, thus granting permission for activated metabolism. During starvation leptin turns down metabolic rate so that a person does not perish from a metabolism that is running too fast when there is not enough available food. Virtually all overweight individuals are stuck in a false state of perceived starvation, driven by leptin resistance. In this state the normal desire to acquire food is turned into addictive food cravings with plasticity changes to nerves that reinforce “learned addiction” for improper food acquisition. Fat cells loose their normal metabolic regulation, excessively expanding and inducing the excessive production of cholesterol and induction of plaque formation in arteries. Thyroid hormone activation is blunted, regardless of blood levels of thyroid hormones. In order to overcome multiple metabolic catch 22s it is vital to return leptin rhythms and function to normal. The foundation of this strategy is based on the patterns of eating that need to be restored. When a person eats is as important as what they eat.

The following information is a combination of the presentation slides and relevant references for each point. The slides used during the presentation will not have the references on them.

Leptin is the hormone that links fat cells and the brain as a metabolic regulator

Full scientific abstracts relating to presentation:

Recent advances indicate that a robust physiologic system acts to maintain relative constancy of weight in mammals. A key component of this system is leptin. Leptin is an adipocyte hormone that functions as the afferent signal in a negative feedback loop regulating body weight. In addition, leptin functions as a key link between nutrition and the function of most, if not all other physiologic systems. When at their set point, individuals produce a given amount of leptin and in turn maintain a state of energy balance. Weight gain results in an increased plasma leptin level, which elicits a biologic response characterized in part by a state of negative energy balance. Weight loss among both lean and obese subjects results in decreased plasma levels of leptin, which lead to a state of positive energy balance and a number of other physiologic responses. In humans, both the intrinsic sensitivity to leptin and its rate of production vary and both appear to contribute to differences in weight. Further studies of leptin, its receptor, and the molecular components of this system are likely to have a major impact on our understanding of obesity and the interplay between nutrition and physiology.

Food intake is regulated via neural circuits located in the hypothalamus. During
the past decade our knowledge on the specific mediators and neuronal networks
that regulate food intake and body weight has increased dramatically. An
important contribution to the understanding of hypothalamic control of food
intake has been the characterization of the ob gene product (leptin) via
positional cloning. Absence of circulating, functionally active, leptin hormone
results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake
and increases energy expenditure via an interaction with specific leptin
receptors located in the hypothalamus. Leptin receptors, of which there are
several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of
cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese
db/db mice, which have a mutation in the db locus, are unable to perform
JAK-STAT signal transduction due to absence of functionally active (long form;
Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with
particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei
and in the lateral hypothalamic area. The abundance of leptin receptors in the
ventromedial and lateral hypothalamus supports early observations that these two
regions are intimately associated with the regulation of food intake. Leptin
receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide
(AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated
transcript (CART)-containing neurons of the ventromedial and ventrolateral
arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and
hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting
that the above-mentioned messengers are mediators of leptin’s action in the
hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived
peptides, CART, MCH, and hypocretins/orexins all are important regulators of
food intake. Leptin is essential for normal body weight balance, but the exact
mechanisms by which leptin activates hypothalamic neuronal circuitries is known
to a limited extent. In order to find pharmaceutical approaches to treat
obesity, further studies will be needed to reveal the exact mechanisms by which
leptin lowers body weight and which role leptin and leptin receptors have in the
pathogenesis of human obesity.

Department of Nutrition, University of California, Davis 95616, USA.
pjhavel@ucdavis.edu

Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor alpha, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.

Obesity is associated with leptin resistance as evidenced by hyperleptinemia.
Resistance arises from impaired leptin transport across the blood-brain barrier
(BBB), defects in leptin receptor signaling, and blockades in downstream
neuronal circuitries. The mediator of this resistance is unknown. Here, we show
that milk, for which fats are 98% triglycerides, immediately inhibited leptin
transport as assessed with in vivo, in vitro, and in situ models of the BBB.
Fat-free milk and intralipid, a source of vegetable triglycerides, were without
effect. Both starvation and diet-induced obesity elevated triglycerides and
decreased the transport of leptin across the BBB, whereas short-term fasting
decreased triglycerides and increased transport. Three of four triglycerides
tested intravenously inhibited transport of leptin across the BBB, but their
free fatty acid constituents were without effect. Treatment with gemfibrozil, a
drug that specifically reduces triglyceride levels, reversed both
hypertriglyceridemia and impaired leptin transport. We conclude that
triglycerides are an important cause of leptin resistance as mediated by
impaired transport across the BBB and suggest that triglyceride-mediated leptin
resistance may have evolved as an anti-anorectic mechanism during starvation.
Decreasing triglycerides may potentiate the anorectic effect of leptin by
enhancing leptin transport across the BBB.

Institute of Physiology, University of Lausanne, Switzerland.
Eric.Jequier@iphysiol.unil.ch

A chronic minor imbalance between energy intake and energy expenditure may lead
to obesity. Both lean and obese subjects eventually reach energy balance and
their body weight regulation implies that the adipose tissue mass is “sensed”,
leading to appropriate responses of energy intake and energy expenditure. The
cloning of the ob gene and the identification of its encoded protein, leptin,
have provided a system signaling the amount of adipose energy stores to the
brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic
receptors to inhibit feeding and increase thermogenesis. A feedback regulatory
loop with three distinct steps has been identified: (1) a sensor (leptin
production by adipose cells) monitors the size of the adipose tissue mass; (2)
hypothalamic centers receive and integrate the intensity of the leptin signal
through leptin receptors (LRb); (3) effector systems, including the sympathetic
nervous system, control the two main determinants of energy balance-energy
intake and energy expenditure. While this feedback regulatory loop is well
established in rodents, there are many unsolved questions about its
applicability to body weight regulation in humans. The rate of leptin production
is related to adiposity, but a large portion of the interindividual variability
in plasma leptin concentration is independent of body fatness. Gender is an
important factor determining plasma leptin, with women having markedly higher
leptin concentrations than men for any given degree of fat mass. The ob mRNA
expression is also upregulated by glucocorticoids, whereas stimulation of the
sympathetic nervous system results in its inhibition. Furthermore, leptin is not
a satiety factor in humans because changes in food intake do not induce
short-term increases in plasma leptin levels. After its binding to LRb in the
hypothalamus, leptin stimulates a specific signaling cascade that results in the
inhibition of several orexigenic neuropeptides, while stimulating several
anorexigenic peptides. The orexigenic neuropeptides that are downregulated by
leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins,
and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are
upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone),
which acts on MC4R (melanocortin-4 receptor); CART (cocaine and
amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone).
Obese humans have high plasma leptin concentrations related to the size of
adipose tissue, but this elevated leptin signal does not induce the expected
responses (i.e., a reduction in food intake and an increase in energy
expenditure). This suggests that obese humans are resistant to the effects of
endogenous leptin. This resistance is also shown by the lack of effect of
exogenous leptin administration to induce weight loss in obese patients. The
mechanisms that may account for leptin resistance in human obesity include a
limitation of the blood-brain-barrier transport system for leptin and an
inhibition of the leptin signaling pathways in leptin-responsive hypothalamic
neurons. During periods of energy deficit, the fall in leptin plasma levels
exceeds the rate at which fat stores are decreased. Reduction of the leptin
signal induces several neuroendocrine responses that tend to limit weight loss,
such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone
levels. Conversely, it is unlikely that leptin has evolved to prevent obesity
when plenty of palatable foods are available because the elevated plasma leptin
levels resulting from the increased adipose tissue mass do not prevent the
development of obesity. In conclusion, in humans, the leptin signaling system
appears to be mainly involved in maintenance of adequate energy stores for
survival during periods of energy deficit. Its role in the etiology of human
obesity is only demonstrated in the very rare situations of absence of the
leptin signal (mutations of the leptin gene or of the leptin receptor gene),
which produces an internal perception of starvation and results in a chronic
stimulation of excessive food intake.

Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional
Genomics, School of Clinical Sciences, University of Liverpool, UK.
p.trayhurn@liverpool.ac.uk

White adipose tissue is now recognised to be a multifunctional organ; in
addition to the central role of lipid storage, it has a major endocrine function
secreting several hormones, notably leptin and adiponectin, and a diverse range
of other protein factors. These various protein signals have been given the
collective name ‘adipocytokines’ or ‘adipokines’. However, since most are
neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term
‘adipokine’ be universally adopted to describe a protein that is secreted from
(and synthesised by) adipocytes. It is suggested that the term is restricted to
proteins secreted from adipocytes, excluding signals released only by the other
cell types (such as macrophages) in adipose tissue. The adipokinome (which
together with lipid moieties released, such as fatty acids and prostaglandins,
constitute the secretome of fat cells) includes proteins involved in lipid
metabolism, insulin sensitivity, the alternative complement system, vascular
haemostasis, blood pressure regulation and angiogenesis, as well as the
regulation of energy balance. In addition, there is a growing list of adipokines
involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming
growth factor-beta, nerve growth factor) and the acute-phase response
(plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of
these proteins by adipose tissue is increased in obesity, and raised circulating
levels of several acute-phase proteins and inflammatory cytokines has led to the
view that the obese are characterised by a state of chronic low-grade
inflammation, and that this links causally to insulin resistance and the
metabolic syndrome. It is, however, unclear as to the extent to which adipose
tissue contributes quantitatively to the elevated circulating levels of these
factors in obesity and whether there is a generalised or local state of
inflammation. The parsimonious view is that the increased production of
inflammatory cytokines and acute-phase proteins by adipose tissue in obesity
relates primarily to localised events within the expanding fat depots. It is
suggested that these events reflect hypoxia in parts of the growing adipose
tissue mass in advance of angiogenesis, and involve the key controller of the
cellular response to hypoxia, the transcription factor hypoxia inducible
factor-1.

Department of Biochemistry and Molecular Biology, University College London,
Gower Street, London WC1E 6BT, United Kingdom.

Insulin resistance, obesity, and diabetes are characterized by hyperglycemia,
hyperinsulinemia, and hyperleptinemia and are associated with increased risk of
atherosclerosis. In an effort to understand how this occurs, we have
investigated whether these factors cause disregulation of cholesterol ester
metabolism in J774.2 macrophages. Raising glucose levels alone was sufficient to
increase uptake of acetylated low density lipoprotein but did not stimulate
synthesis of cholesterol esters. In the presence of high glucose, both insulin
and leptin increased the rate of cholesterol ester synthesis, although they did
not further increase uptake of acetylated low density lipoprotein. However, in
the presence of high glucose both insulin and leptin caused a significant
increase in the activity of acyl-CoA: cholesterol O-acyltransferase (ACAT)
combined with a significant reduction in the level of hormone-sensitive lipase
(HSL). Because ACAT is the main enzyme responsible for cholesterol ester
synthesis and HSL contributes significantly to neutral cholesterol ester
hydrolase activity, this suggests that glucose primes the J774.2 cells so that
in the presence of high insulin or leptin they will store cholesterol esters.
This contrasts with 3T3-L1 adipocytes, where HSL activity and expression are
increased by insulin in high glucose conditions. These findings may provide an
explanation for the observation that in conditions characterized by
hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in
adipocytes is increased while hydrolysis of cholesterol esters in macrophages is
decreased, contributing to foam cell formation.

Regulation of the hypothalamic-pituitary-thyroid (HPT) axis is dependent upon
the secretion of thyrotropin-releasing hormone (TRH), a tripeptide originating
in the hypothalamic paraventricular nucleus (PVN). These so-called
hypophysiotropic neurons are under feedback inhibition by circulating levels of
thyroid hormone, mediated through interactions with the beta2 thyroid hormone
receptor (TRbeta2) and competition with the phosphorylated form of cyclic
adenosine 5’-monophosphate response element binding protein (CREB) for a
multifunctional binding site in the TRH gene. The non-thyroidal illness
syndrome, characterized by low circulating thyroid hormone levels yet
suppression of TRH gene expression in hypophysiotropic neurons, is due to
alteration in the regulatory factors that modulate TRH gene expression to result
in central hypothyroidism. These factors include alpha melanocyte-stimulating
hormone (alphaMSH) and cocaine- and amphetamine-regulated transcript (CART), and
agouti-related protein (AGRP) and neuropeptide Y (NPY), substances co-produced
by distinct populations of leptin-responsive neurons in the hypothalamic arcuate
nucleus. Through monosynaptic projections from arcuate nucleus neurons to
hypophysiotropic TRH neurons, these factors contribute to suppression of HPT
axis during fasting and starvation by exerting opposing actions on the TRH gene,
altering the sensitivity for feedback inhibition by thyroid hormone. In
contrast, central hypothyroidism associated with infection may be due to
upregulation of type 2 deiodinase activity in tanycytes, specialized glial cells
that line the infralateral walls and floor of the third ventricle. Through
tanycyte-cerebrospinal fluid, -vascular or -neuronal associations, these cells
may lead to inhibition of TRH gene expression in hypophysiotropic neurons by
increasing local triiodothyronine production.

Obesity may be a low-grade systemic inflammatory disease. Overweight and obese
children and adults have elevated serum levels of C-reactive protein,
interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers
of inflammation and closely associated with cardiovascular risk factors and
cardiovascular and non-cardiovascular causes of death. This may explain the
increased risk of diabetes, heart disease, and many other chronic diseases in
the obese. The complex interaction between several neurotransmitters such as
dopamine, serotonin, neuropeptide Y, leptin, acetylcholine,
melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin
and insulin receptors in the brain ultimately determines and regulates food
intake. Breast-feeding of more than 12 mo is associated with decreased incidence
of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty
acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs
inhibit the production of proinflammatory cytokines and enhance the number of
insulin receptors in various tissues and the actions of insulin and several
neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic
proteins, which participate in neurogenesis, so these fatty acids might play an
important role in brain development and function. It is proposed that obesity is
a result of inadequate breast feeding, which results in marginal deficiency of
LCPUFAs during the critical stages of brain development. This results in an
imbalance in the structure, function, and feedback loops among various
neurotransmitters and their receptors, which ultimately leads to a decrease in
the number of dopamine and insulin receptors in the brain. Hence, promoting
prolonged breast feeding may decrease the prevalence of obesity. Exercise
enhances parasympathetic tone, promotes antiinflammation, and augments brain
acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine
and insulin inhibit the production of proinflammatory cytokines and provide a
negative feedback loop for postprandial inhibition of food intake, in part, by
regulating leptin action. Statins, peroxisome proliferator-activated
receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant
formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress
inflammation, may be beneficial in obesity.

Obesity is a major risk factor associated with a variety of human disorders.
While its involvement in disorders such as diabetes, coronary heart disease and
cancer have been well characterized, it remains to be determined if obesity has
a detrimental effect on the nervous system. To address this issue we determined
whether obesity serves as a risk factor for neurotoxicity. Model neurotoxicants,
methamphetamine (METH) and kainic acid (KA), which are known to cause selective
neurodegeneration of anatomically distinct areas of the brain, were evaluated
using an animal model of obesity, the ob/ob mouse. Administration of METH and KA
resulted in mortality among ob/ob mice but not among their lean littermates.
While METH caused dopaminergic nerve terminal degeneration as indicated by
decreased striatal dopamine (49%) and tyrosine hydroxylase protein (68%), as
well as an increase in glial fibrillary acidic protein by 313% in the lean mice,
these effects were exacerbated under the obese condition (96%, 86% and 602%,
respectively). Similarly, a dosage of KA that did not increase glial fibrillary
acidic protein in lean mice increased the hippocampal content of this protein
(93%) in ob/ob mice. KA treatment resulted in extensive neuronal degeneration as
determined by Fluoro-Jade B staining, decreased hippocampal
microtubule-associated protein-2 immunoreactivity and increased reactive gliosis
in ob/ob mice. The neurotoxic outcome in ob/ob mice remained exacerbated even
when lean and ob/ob mice were dosed with METH or KA based only on a lean body
mass. Administration of METH or KA resulted in up-regulation of the
mitochondrial uncoupling protein-2 to a greater extent in the ob/ob mice, an
effect known to reduce ATP yield and facilitate oxidative stress and
mitochondrial dysfunction. These events may underlie the enhanced neurotoxicity
seen in the obese mice.In summary, our results implicate obesity as a risk
factor associated with chemical- and possibly disease-induced neurodegeneration.

Feeding is a complex process responsive to sensory information related to sight
and smell of food, previous feeding experiences, satiety signals elicited by
ingestion and hormonal signals related to energy balance. Dopamine released in
specific brain regions is associated with pleasurable and rewarding events and
may reinforce positive aspects of feeding. Dopamine also influences initiation
and coordination of motor activity and is required for sensorimotor functions.
Thus, dopamine may facilitate integration of sensory cues related to hunger,
initiating the search for food and its consumption. Dopaminergic neurons in the
substantia nigra and ventral tegmental area project to the caudate putamen and
nucleus accumbens, where they modulate movement and reward. There are
projections from the nucleus accumbens to the lateral hypothalamus that regulate
feeding. Dopamine-deficient mice (Dbh(Th/+), Th-/-; hereafter DD mice) cannot
synthesize dopamine in dopaminergic neurons. They gradually become aphagic and
die of starvation. Daily treatment of DD mice with L-3,4-dihydroxyphenylalanine
(L-DOPA) transiently restores brain dopamine, locomotion and feeding.
Leptin-null (Lep(ob/ob)) mice exhibit obesity, decreased energy expenditure and
hyperphagia. As the hypothalamic leptin-melanocortin pathway appears to regulate
appetite and metabolism, we generated mice lacking both dopamine and leptin (DD
x Lep(ob/ob)) to determine if leptin deficiency overcomes the aphagia of DD
mice. DD x Lep(ob/ob) mice became obese when treated daily with L-DOPA, but when
L-DOPA treatment was terminated the double mutants were capable of movement, but
did not feed. Our data show that dopamine is required for feeding in leptin-null
mice.

The involvement of the satiety-controlling hormone leptin in the modulation of the reward-associated dopamine release was investigated by monitoring the extracellular dopamine concentration in microdialysates from the nucleus accumbens of rats during feeding after infusion of leptin or artificial cerebrospinal fluid into the lateral ventricle of rats. Leptin suppressed the basal as well as the feeding-evoked extracellular dopamine concentration and reduced the amount and duration of food intake compared to the pair-feed vehicle-treated controls. These results suggest that leptin is involved in the dopaminergic modulation of feeding-induced rewarding functions.

Fishberg Center for Neurobiology, Department of Geriatrics, Mount Sinai School
of Medicine, New York, New York, USA.

In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or
attenuates the obese phenotype. Relative to lean controls, ob/ob mice also
exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased
hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA.
It has been hypothesized that this profile of hypothalamic gene expression
contributes to the obese phenotype caused by leptin deficiency. To assess if
reversal of obese phenotype by adrenalectomy entails normalization of
hypothalamic gene expression, male wild-type and ob/ob mice were
adrenalectomized (with saline supplementation) or sham adrenalectomized at 2
months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which
time food intake and body weight were monitored daily. After sacrifice,
hypothalamic gene expression was assessed by Northern blot analysis as well as
in situ hybridization. In wild-type mice, adrenalectomy significantly decreased
AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice,
adrenalectomy reduced the levels of plasma glucose, serum insulin and
corticosterone, and food intake toward or below wild-type levels, and it
restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese
phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone
toward wild-type levels. These studies also demonstrate that factors other than
leptin may play a major role in regulating hypothalamic melanocortin function.

Drug addiction manifests as a compulsive drive to take a drug despite serious
adverse consequences. This aberrant behaviour has traditionally been viewed as
bad “choices” that are made voluntarily by the addict. However, recent studies
have shown that repeated drug use leads to long-lasting changes in the brain
that undermine voluntary control. This, combined with new knowledge of how
environmental, genetic and developmental factors contribute to addiction, should
bring about changes in our approach to the prevention and treatment of
addiction.

Department of Molecular Physiology and Biophysics, Vanderbilt University School
of Medicine, Nashville, TN 37232-0615, USA. Danny.winder@vanderbilt.edu

Drug addiction is a major public health issue worldwide. The persistence of drug
craving coupled with the known recruitment of learning and memory centers in the
brain has led investigators to hypothesize that the alterations in glutamatergic
synaptic efficacy brought on by synaptic plasticity may play key roles in the
addiction process. Here we review the present literature, examining the
properties of synaptic plasticity within drug reward circuitry, and the effects
that drugs of abuse have on these forms of plasticity. Interestingly, multiple
forms of synaptic plasticity can be induced at glutamatergic synapses within the
dorsal striatum, its ventral extension the nucleus accumbens, and the ventral
tegmental area, and at least some of these forms of plasticity are regulated by
behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the
present data suggest that regulation of synaptic plasticity in reward circuits
is a tractable candidate mechanism underlying aspects of addiction.

Department of Psychiatry and Center for Basic Neuroscience, The University of
Texas Southwestern Medical Center, Dallas 75390-9070, USA.
eric.nestler@utsouthwestern.edu

Drugs of abuse cause long-lasting changes in the brain that underlie the
behavioral abnormalities associated with drug addiction. Similarly, experience
can induce memory formation by causing stable changes in the brain. Over the
past decade, the molecular and cellular pathways of drug addiction, on the one
hand, and of learning and memory, on the other, have converged. Learning and
memory and drug addiction are modulated by the same neurotrophic factors, share
certain intracellular signaling cascades, and depend on activation of the
transcription factor CREB. They are associated with similar adaptations in
neuronal morphology, and both are accompanied by alterations in synaptic
plasticity (e.g., long-term potentiation, long-term depression) at particular
glutamatergic synapses in the brain. There has also been recent convergence in
the brain regions now considered important sites for molecular and cellular
plasticity underlying addiction and memory. Complex circuits involving the
hippocampus, cerebral cortex, ventral and dorsal striatum, and amygdala are
implicated both in addiction and in learning and memory. The complexity of the
plasticity that occurs in these circuits can be illustrated by CREB, which
induces very different behavioral effects in these various brain regions. A
better understanding of the molecular and cellular adaptations that occur in
these neural circuits may lead to novel interventions to improve memory and
combat addiction in humans. Copyright 2002 Elsevier Science (USA)

Leptin is a hormone that regulates body weight homeostasis mainly via the
hypothalamic functional leptin receptor Ob-Rb. Recently, we proposed that the
taste organ is a new peripheral target for leptin. Leptin selectively inhibits
mouse taste cell responses to sweet substances and thereby may act as a sweet
taste modulator. The present study further investigated leptin action on the
taste system by examining expression of Ob-Rb in taste cells and behavioral
responses to sweet substances in leptin-deficient ob/ob, and Ob-Rb-deficient
db/db mice and their normal litter mates. RT-PCR analysis showed that Ob-Rb was
expressed in taste cells in all strains tested. The db/db mice, however, had a
RT-PCR product containing an abnormal db insertion that leads to an impaired
shorter intracellular domain. In situ hybridization analysis showed that the
hybridization signals for normal Ob-Rb mRNA were detected in taste cells in lean
and ob/ob mice but not in db/db mice. Two different behavioral tests, one using
sweet-bitter mixtures as taste stimuli and the other a conditioned taste
aversion paradigm, demonstrated that responses to sucrose and saccharin were
significantly decreased after ip injection of leptin in ob/ob and normal
littermates, but not in db/db mice. These results suggest that leptin suppresses
behavioral responses to sweet substances through its action on Ob-Rb in taste
cells. Such taste modulation by leptin may be involved in regulation for food
intake.

Conditioned environmental stimuli are known to be important determinants of drug
seeking. Traditional models of drug seeking under the control of conditioned
stimuli have focused on the ability of conditioned reinforcers either to
reinstate extinguished responding or to maintain prolonged chains of drug
seeking under second-order schedules. These models have consistently suggested
that it is the conditioned reinforcing, rather than other, effects of Pavlovian
drug stimuli that most profoundly influence drug seeking. However, the impact of
drug-associated conditioned reinforcers has not been studied directly and in
isolation, not least because the instrumental seeking response is invariably the
same as that which was previously reinforced with the drug itself. The purpose
of the present study was, therefore, to investigate the conditioned reinforcing
properties of drug-paired CSs using an acquisition of a new response procedure
in which an animal learns to make a new instrumental response reinforced solely
by the CS. It was found that CSs paired with either cocaine, heroin or sucrose
supported the rapid acquisition of lever pressing for the CS that persisted over
months of repeated, intermittent testing. Furthermore, rats did not acquire the
lever press response when the CS was not paired with drug, suggesting that for
this stimulus to acquire conditioned reinforcing properties, it must be
predictively associated with the drug’s effect. Moreover, lever pressing for the
CS could not be explained as coincidental to an over-riding Pavlovian approach
response to the location of the lever, since animals also acquired discriminated
lever pressing when the CS was above the opposite, inactive lever. Extinction
decreased responding with conditioned reinforcement, but only when the CS-US
association was devalued prior to, and not after, acquisition of the lever press
response, providing evidence for the establishment of habitual CS-maintained
responding that may explain the persistence of drug-seeking responses in animal
models of addiction and relapse.

Overeating in obese individuals shares similarities with the loss of control and
compulsive drug taking behavior observed in drug-addicted subjects. The
mechanism of these behaviors is not well understood. Our prior studies with
positron emission tomography (PET) in drug-addicted subjects documented
reductions in striatal dopamine (DA) D2 receptors. In pathologically obese
subjects, we found reductions in striatal DA D2 receptors similar to that in
drug-addicted subjects. Moreover, DA D2 receptor levels were found to have an
inverse relationship to the body mass index of the obese subjects. We postulated
that decreased levels of DA D2 receptors predisposed subjects to search for
reinforcers; in the case of drug-addicted subjects for the drug and in the case
of the obese subjects for food as a means to temporarily compensate for a
decreased sensitivity of DA D2 regulated reward circuits. Understanding the
mechanism in food intake will help to suggest strategies for the treatment of
obesity.

Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005 Feb;5(1):70-5.

Diabetes and Metabolism Translational Medicine Unit, Division of Endocrinology
and Metabolism, Department of Medicine, University of Vermont College of
Medicine, FAHC/UHC—Arnold 3412, One South Prospect Street, Burlington, VT
05401, USA. ylee@uvm.edu

Advances in adipose tissue biology over the past 10 years have led to an
improved understanding of the mechanisms linking obesity with the metabolic
syndrome and other complications. Obesity is characterized by a chronic,
systemic low-grade state of inflammation. Biomarkers of inflammation, such as
the leukocyte count, tumor necrosis factor-alpha (TNF-alpha), interleukin 6
(IL-6), and C-reactive protein, are increased in obesity, associated with
insulin resistance, and predict the development of type 2 diabetes and
cardiovascular disease. It is now clear that the adipocyte is an active
participant in the generation of the inflammatory state in obesity. Adipocytes
secrete a variety of cytokines, including IL-6 and TNF-alpha, that promote
inflammation. Moreover, recent studies suggest that obesity is associated with
an increase in adipose tissue macrophages, which also participate in the
inflammatory process through the elaboration of cytokines. An improved
understanding of the role of adipose tissue in the activation of inflammatory
pathways may suggest novel treatment and prevention strategies aimed at reducing
obesity-associated morbidities and mortality.

Sterol regulatory element-binding proteins (SREBPs) have been established as
lipid synthetic transcription factors for cholesterol and fatty acid synthesis.
SREBPs are synthesized as membrane-bound precursors with their N-terminal active
portions entering the nucleus to activate target genes after proteolytic
cleavage in a sterol-regulated manner. This cleavage step is regulated by a
putative sterol-sensing molecule, SREBP-activating protein (SCAP), that forms a
complex with SREBPs and traffics between the rough endoplasmic reticulum and
Golgi. DNA cis-elements that SREBPs bind, originally identified as
sterol-regulatory elements (SREs), now expands to a variety of SRE-like
sequences and some of E-boxes, which makes SREBPs eligible to regulate a wide
range of lipid genes. Animal experiments including transgenic and knockout mice
suggest that three isoforms, SREBP-1a, -1c, and -2, have different roles in
lipid synthesis. In differentiated tissues and organs, SREBP-1c is involved in
fatty acid, whereas SREBP-2 plays a major role in regulation of cholesterol
synthesis. SREBP-1a is expressed in growing cells, providing both cholesterol
and fatty acids that are required for membrane synthesis. SREBP-1c seems to be a
mediator for insulin/glucose signaling to lipogenesis, and could be involved in
insulin resistance, remnant lipoproteins, and fatty livers. Future studies in
this field will certainly focus on understanding the molecular mechanisms
sensing cellular sterol and energy states leading to the activation of
SREBP-mediated gene transcription.

Lipid accumulation by vascular smooth muscle cells (VSMC) is a feature of
atherosclerotic plaques. In this study we describe two mechanisms whereby human
VSMC foam cell formation is driven by de novo synthesis of fatty acids leading
to triacylglycerol accumulation in intracellular vacuoles, a process distinct
from serum lipoprotein uptake. VSMC cultured in adipogenic differentiation
medium accumulated lipids and were induced to express the adipocyte marker genes
adipsin, adipocyte fatty acid-binding protein, C/EBPalpha, PPARgamma, and
leptin. However, complete adipocyte differentiation was not observed as numerous
genes present in mature adipocytes were not detected, and the phenotype was
reversible. The rate of lipid accumulation was not affected by PPARgamma
agonists, but screening for the effects of other nuclear receptor agonists
showed that activation of the liver X receptors (LXR) dramatically promoted
lipid accumulation in VSMC. Both LXRalpha and LXRbeta were present in VSMC, and
their activation with TO901317 resulted in induction of the lipogenic genes
fatty acid synthetase, sterol regulatory element binding protein (SREBP1c), and
stearoyl-CoA desaturase. 27-Hydroxycholesterol, an abundant oxysterol
synthesized by VSMC acted as an LXR antagonist and, therefore, may have a
protective role in preventing foam cell formation. Immunohistochemistry showed
that VSMC within atherosclerotic plaques express adipogenic and lipogenic
markers, suggesting these pathways are present in vivo. Moreover, the
development of an adipogenic phenotype in VSMC is consistent with their known
phenotypic plasticity and may contribute to their dysfunction in atherosclerotic
plaques and, thus, impinge on plaque growth and stability.

Euthyroid sick syndrome, characterized by low serum 3,5, 3’-triiodothyronine
(T(3)) with normal L-thyroxine levels, is associated with a wide variety of
disorders including sepsis, malignancy, and AIDS. The degree of low T(3) in
circulation has been shown to correlate with the severity of the underlying
disorders and with the prognosis. Elevated TNF-alpha levels, which accompany
severe illness, are associated with decreased activity of type I 5’-deiodinase
(5’-DI) in liver, leading us to speculate that high levels of this factor
contribute to euthyroid sick syndrome. Here we demonstrate that the activation
of NF-kappa B by TNF-alpha interferes with thyroid-hormone action as
demonstrated by impairment of T(3)-dependent induction of 5’-DI gene expression
in HepG2 cells. Inhibition of NF-kappa B action by a dominant-negative NF-kappa
B reversed this effect and allowed T(3) induction of 5’-DI. Furthermore, we show
that an inhibitor of NF-kappa B activation, clarithromycin (CAM), can inhibit
TNF-alpha-induced activation of NF-kappa B and restore T(3)-dependent induction
of 5’-DI mRNA and enzyme activity. These results suggest that NF-kappa B
activation by TNF-alpha is involved in the pathogenesis of euthyroid sick
syndrome and that CAM could help prevent a decrease in serum T(3) levels and
thus ameliorate euthyroid sick syndrome.

Department of Molecular Biology and Biochemistry, University of California,
Irvine, California 92697-3900, USA.

High affinity uptake of serum-derived low density lipoprotein (LDL) cholesterol
is accomplished through the LDL receptor in the liver. In mammals, thyroid
hormone depletion leads to decreased LDL receptor expression and elevated serum
cholesterol. The clinical association in humans has been known since the 1920s;
however, a molecular explanation has been lacking. LDL receptor levels are
subject to negative feedback regulation by cellular cholesterol through sterol
regulatory element-binding protein-2 (SREBP-2). Here we demonstrate that the
SREBP-2 gene is regulated by thyroid hormone and that increased SREBP-2 nuclear
protein levels in hypothyroid animals results in thyroid hormone-independent
activation of LDL receptor gene expression and reversal of the associated
hypercholesterolemia. This occurs without effects on other thyroid
hormone-regulated genes. Thus, we propose that the decreased LDL receptor and
increased serum cholesterol associated with hypothyroidism are secondary to the
thyroid hormone effects on SREBP-2. These results suggest that
hypercholesterolemia associated with hypothyroidism can be reversed by agents
that directly increase SREBP-2. Additionally, these results indicate that
mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia.

Department of Human Nutrition and Nutritional Biology, The University of
Chicago, Chicago, Illinois 60637, USA.

To identify the physiologic factor(s) that entrain the diurnal rhythm of plasma
leptin, leptin levels were measured hourly after changes in light/dark cycle,
sleep/wake cycle, and meal timing. Four young male subjects were studied during
each of two protocols, those being a simulated 12-h time zone shift and a 6.5-h
meal shift. During the baseline day, plasma leptin demonstrated a strong diurnal
rhythm with an amplitude of 21%, zenith at 2400 h, and nadir between 0900 and
1200 h. Acute sleep deprivation did not alter plasma leptin, but day/night
reversal (time zone shift)

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